Bendamustine (4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazo-2-yl]butanoic acid, a nitrogen mustard) is an alkylating agent with bifunctional alkylating activity. It corresponds to the following formula (I):
Bendamustine appears to be free of any cross-resistance with other alkylating agents, which offers advantages in terms of chemotherapy for patients who have already received treatment with an alkylating agent.
Bendamustine was initially synthesized in the German Democratic Republic (GDR). The hydrochloric acid of bendamustine was the active ingredient in a commercial product available from 1971 to 1992 under the trade name Cytostasan®. Since that time, it has been marketed in Germany under the trade name Ribomustin® and has been widely used to treat chronic lymphocytic leukemia, non-Hodgkin's lymphoma and multiple myeloma.
The marketed product contains a lyophilized powder of bendamustine hydrochloride which is reconstituted with water for injection yielding a concentrate. This is subsequently diluted with an aqueous solution of 0.9% sodium chloride resulting in the final solution for infusion. This final solution is administered to the patient by intravenous infusion over a period of about 30 to 60 minutes.
Hydrolysis of the bis-2-chloroethylamino-group of bendamustine in water leads to reduction in potency and to impurity formation (B. Maas et al. (1994) in Pharmazie 49: 775-777). Hence administration, usually in a hospital or at least under medical supervision, must occur immediately after reconstitution of the lyophilized powder. Furthermore, reconstitution has been reported to be difficult. It may require more than 30 minutes. Further, it is burdensome and time-consuming for the healthcare professionals responsible for reconstituting the product in the 2 step process.
Preiss et al. (1985) in Pharmazie 40:782-784 compared the pharmacokinetics of bendamustine hydrochloride in plasma in 7 patients after intravenous and oral administration respectively in a dose ranging between 4.2-5.5 mg/kg. The intravenous infusion prepared from the commercially available Cytostasan® product was given over 3 minutes, whereas oral medication in an equivalent dose was taken in the form of capsules, containing 25 mg of bendamustine hydrochloride. The number of capsules to be taken by the patients varied from 10-14, referring to absolute oral doses of 250-350 mg. After oral administration maximal plasma levels were detectable within 1 hour. The mean oral bioavailability was calculated to be 57%, ranging from 25% to 94% indicating a large inter-individual variability (% CV=44%).
Weber (1991) (Pharmazie 46(8): 589-591) investigated the bioavailability of bendamustine hydrochloride in B6D2F1-mice and found that the absorption of the drug from the gastro-intestinal tract is incomplete resulting in a bioavailability of about 40% only.
US 2006/0128777 A1 describes methods for treating cancers, characterised by death-resistant cells and bendamustine-containing compositions in general. Amongst these compositions are oral dosage forms, which are capsules, tablets, pills, powders or granules, wherein the active compound may be admixed with at least one inert excipient, such as sucrose, lactose or starch. However, specific compositions were not exemplified.
Bendamustine hydrochloride is only sparingly soluble in water at a pH of 2.0 and is slightly or very slightly soluble in a range of organic solvents. A good solubility has been observed however in ethanol and methanol. Therefore it is not surprising that the oral bendamustine compositions, as investigated by Preiss et al. and Weber gave rise to relatively poor bioavailability results and a large inter-individual variability.
In view of the stability problems with the intravenous marketed formulation, once reconstituted with water, and in order to improve the patient compliance there has been a long-felt need for a stable dosage-form comprising bendamustine which is easy to administer to the patient and which provides good bioavailability without large inter- and intra-individual variability.